IE44792B1 - Heterocyclic derivatives of guanidine - Google Patents

Abstract

Heterocyclic guanidine derivatives of the formula I in which the symbols are defined in Claim 1, and their pharmaceutically acceptable acid addition salts, are obtained by reacting a corresponding compound, possessing an alkylthio radical instead of the group -NR4R5, with an amine HNR4R5 in a lower aliphatic alcohol at reflux temperature and converting the resulting salt of the compound of the formula I into the free base and, where appropriate, preparing pharmaceutically acceptable acid addition salts from compounds obtained. The quaternary products can also be prepared. The compounds of the formula I, their salts and the quaternisation products, inhibit, for example, gastric juice secretion and lower blood sugar level. They can be used as medicaments.

Description

The present invention relates to heterocyclic derivatives of guanidine having antisecretory and hypoglycemic activity.

British Patent Specification No 1,409,768 describes 5 several heterocyclic derivatives of guanidine in which the heterocyclic moiety is a 5- or 6-membered saturated 1,3diazacarbocyclic-2-ylidene. These derivatives are unsubstituted on the imino nitrogen of the guanidine moiety. In contrast, the compounds of the present invention, as hereinafter defined, differ by being saturated mono-aza heterocyclic derivatives of guanidine, which furthermore, carry a bulky substituent on the imino nitrogen of the guanidine moiety. Additional related prior art is German Offenlegungsschrift No. 2,321,330 and German Offenlegungsschrift No. 2,502,397.

The present invention provides heterocyclic derivatives of guanidine having the general formula: wherein: n is the integer 1, 2 or 3; R^ is a'hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, a cycloalkyl group havxng from 3 to 6 carbon atoms (preferably cyclopentyl or cyclohexyl), an alken-2yl group having from 3 to 5 carbon atoms,a hydroxyloweralkyl (preferably hydroxyethyl), aralkyl (preferably benzyl) or an aryl group (preferably phenyl); R2 is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aryl group (preferably phenyl); R3 is a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms or an aryl group (preferably phenyl); R^ is a hydrogen atom, a methyl or an ethyl group; Rg is an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms (preferably cyclopentyl or cyclohexyl), an aralkyl (preferably benzyl) or aryl group (preferably phenyl or phenyl substituted with from 1 to 3 substituents each selected from a halogen atom, a loweralkyl or loweralkoxy group); or -N \ R5 taken together represents a 3- to 7-membered saturated heterocyclic ring, provided that when -NR^Rg represents a sixmembered ring, (i) the ring may, if desired, be interrupted by an oxygen or sulfur atom or by an additional nitrogen atom, which additional nitrogen atom may be substituted with a loweralkyl, phenyl or benzyl group or (ii) the ring maybe substituted with a lower alkyl group at a carbon atan other than ere dmnediately adjacent tfye nitrogen atom which is bonded to the carboximidamide function, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidino, 2,3,4,5,6,7-hexahydro-azepinyl, morpholi3 47 9 3 no, thiamorpholino, thiamorpholino-l-oxide, thiamorpholino-1, 1-dioxide, 2,6-diloweralkyl-morpholino (preferably 2,6dimethyI-morpholino), 4-lowersIky1-piperazinyl (preferably 4-methy1-piperazinyl), 4-pheny1-piperazinyl, 4-benzyl-pipera5 zinyl or 2,6-diloweralkyl-piperazinyl (preferably 2,6-dimethylpiperazinyl); and R is an alkyl-group having from 4 to 10 carbon atoms (preferably a branched alkyl group such as tert-butvl. neopentyl or 1,1,3,3-tetramethylbutyl); a cycloalkyl having from to 8 carbon atoms (preferably cyclopentyl or cyclohexyl); a bicycloalkyl group having from 7 to 10 carbon atoms, such as exo- and endo-2-norbornvl, 2-bicyclo [2,2.2.]-octyl or.endo-2bicyclo [3.2.1.] octyl;, a bicycloalkenyl group having from 7 to lO carbon atoms, such as anti-7-norborneyl; a tricyclo15 alkyl group having 9 or lo carbon atoms, such as noradamantyl, 1- and 2-adamantyl or 1- and 2-(2,3,3a,4,5,6,7,7aoctahydro-4,7-methanoindanyl); 1-adamantyImethyl; a tricycloalkenyl group having 9 or io carboft atoms, such as 3-(2,3,6,6atetrahvdro-lH-l,3a-ethanopentalenvl) or 5-(3a,4,5,6,7,7a20 hexahydro-4,7-methanoindenyl; an arylalkyl group in which the aryl group is a phenyl Or naphthyl group and the alkyl group has from 1 to 4 carbon atoms, such as benzyl, d- or 1,-aphenethyl, a, a-dimethylbenzyl, a, a-dimethyΙ-β-phenethy1 or d-or J.-(a-naph thyl) ethyl; a,a-tetramethylene-phenethyl; a diphenylaIky1 group in which the alkyl function has 1 or 2 carbon atoms,' such as diphenylmethyl or 2,2-diphenylethyl; · naphthyl (including a- and β-naphthyl); a fused diarylcycloalkenyl group, such as 9-fluorenyl or 5-acenaphthyl; - 4 44792 a fused arylcycloalkyl group, such as 4-(2,3-dihydro-lHindenyl), 1-(1,2,3,4~tetrahydronaphthyl) or 7-(bicyclo [4.2.0] octa-1,3,5-trienyl); a phenylcycloalkyl group in which the cycloalkyl group has from 5 to 7 carbon atoms, such as cis5 or trans-2-phenylcyclopentyl, cis- or trans-2-phenyIcyclohexvl or cis- or trans-2-phenyIcvclohepty 1 ,· a cycloalkylcycloalkyl group in which each cycloalkyl group has from 5 to 7 carbon atoms, such as cis- or trans-2-cvclohexylcyclopentyl or cisor trans-2-cvclopenty1-cyclopentyl; phenyl; methylenedioxy10 phenyl; a phenyl group substituted with from 1 to 3 substituents each selected from a halogen atom, or a loweralkyl or loweralkoxy group, a phenyl group substituted with an amino, dimethyl amino, methylethylamino, diethylamino, loweralkanoylamino, thioloweralkyl, sulfinylloweralkyl, sulfonylloweralkyl, trifluoro15 methyl, hydroxy, benzyloxy, loweralkanoyloxy, loweralkanoyl or nitro group;· 3-pyridyl? or a 3-pyridyl group substituted with 1 or 2 substituents each selected from a halogen atom, or a loweralkyl or loweralkoxy group, such as 6-methoxy-3-pyridyl, 6-chloro-3-pyridyl, 2,6-dimethyl-3-pyridyl, 2,6-dichloro-320 pyridyl or 2,6-dimethoxy-3-pyridyl; and 5-membered heterocyclic groups, such as, for example, 2-furyl and 2-thienyl.

By the prefix lower as used herein is meant that the . relevant group has from 1 to 4 carbons and by the term halo or halogen is meant halogens of atomic weight less than 127, i.e. chloro, bromo, fluoro and iodo. Preferably, when either of the groups R2 or Rg is an alkyl or aryl group, then the other group is a hydrogen atom, and when n is the integer 2 or 3, then preferably R2 and Rg are both hydrogeh atoms. - 5 r Due to the presence of tertiary nitrogen in the compounds of formula· (I), acid addition and quaternary salts thereof are readily obtained and such pharmaceutically acceptable salts are included within the scope of the present invention. The compounds of formula (Ϊ) may be converted into their therapeutically active non-toxic acid addition salts by treatment with an appropriate acid, such as an inorganic acid,for example a hydrohalic acid, e.g. hydrochloric or -hydrobromic acid, and sulfuric acid, nitric acid or phos10 phoric acid, or an organic acid, such as acetic, propionic, glycolic pamoic, pyruvic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methane' sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclohexanesulfamie, salicylic or £-aminosalicylic. Conversely, the acid addition salts can be converted by treatment with alkali into the free bases.

Therapeutically active quaternary ammonium salts may be prepared by reaction of a compound of formula (I) with an alkylating agent, i.e. an alkyl, alkenyl or aralkyl halide, sulfate or sulfonate ester, such as, methyl iodide, ethyl bromide, propyl bromide, allyl chloride, benzyl chloride, a di-loweralkyl sulfate (e.g. diffiethylsulfate or diethylsulfate), a loweralkyl arylsulfonate (e.g. methyl £-toluenesulfonate), or methyl fluorosulfonate. The quaternizing reaction may be carried out in the presence or absence of a solvent, depending on whether or not the quaternizing agent is itself capable of acting as the solvent at room temperature or under cooling, at atmospheric pressure or in a closed vessel under pressure. ' - 6 Suitable reaction-inert organic solvents for this purpose are . iethers such as diethylether and tetrahydrofuran, hydrocarbons such as benzene and heptane, ketones such as acetone and butanone, lower alkanols such as ethanol, propanol and butanol, or organic acid amides such as formamide or dimethylformamide. The anion function of the quaternary salt is readily exchangeable by conventional ion-exchange techniques.

The most preferred compounds of this invention, in view of their ’exceptional hypoglycemic activity, are the com10 pounds of the following general formula: ΙΙΟ' I ’ / ’ =N—C—N 'H R8 (II) and the pharmaceutically acceptable acid addition and quaternary salts thereof wherein: n is an integer of 1 or 2 ‘15 R, is a loweralkyl, allyl, hydroxy-loweralkyl or benzyl b group? Rg is a methyl or ethyl group? R is a loweralkyl, cyclopentyl or cyclohexyl group; or 8 -NR_RO taken together is a pyrrolidino, piperidino, o morpholino or thiamorpholino group; R is a phenyl group, a previously described substituted phenyl group, other than sulfonylloweralkylphenyl, 1-adamantyl and 1,1,3,3-tetramethylbutyl, cyclohexyl, diphenylmethyl, naphthyl and 9-fluoroenyl? Rl0 is a hydrogen atom or an alkyl group of 1 tc 3 carbon - 7 4-^93 : ' atoms; is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms; provided that at least one of R^Q and R^^ is a hydrogen a-f^om. , The; qompounds of formula (I) are conveniently prepared by reacting a lactam salt of formula (III), wherein n, R^, R2 and Rg are as previously defined, X is either methoxy or ethoxy, 0 0 0 and Y is either BF^ or OSOgF , with a guanidine derivative of formula (iv), wherein R, R^, Rg and NR^R^ are as previously defined, stoichiometric quantities of reactants are preferably: employed. Suitable anhydrous organic solvents for conducting the reaction include lower aliphatic alcohols, such as, methanol, ethanol, 2-propanol or tert-butanol; ethers, such as, diethylether, tetrahydrofuran or dioxane; lower halogenated hydrocarbons, such as, chloroform, methylene chloride or 1,2dichloroethane; and aromatic hydrocarbons, such as, benzene, toluene or xylene. Temperatures from 0°C to ambient may generally be employed. The product (V), in the form of the corresponding HY salt, is converted to the corresponding base form (I) by conventional means, for example,.by treatment with a suitable alkali such as an alkali metal or alkaline earth metal hydroxide or carbonate. The reaction may be illustrated as follows; - 8 44792 (III) (IV) alkali (I) Θ The lactam fluoborates of formula (III), wherein Y is θ BF^ , are generally known and may be obtained according to procedures described in the literature, e.g., see Canadian Patents Nos. 850,116 and 950,464; U.S. Patent No, 3,876,658; Ber. 89, 2063 (1956); and Org. Synth. 46, 113, 120 (1966).

Q The lactam fluorosulfonates of formula (III), wherein Y is Θ OSOgF , are similarly prepared. In general, a lactam of formula (VI) is reacted with an appropriate trialkyl oxonium fluoborate (VII) or methyl fluorosulfonate (VIII) to give the corresponding lactam salt. The reaction is preferably carried out from O°C to ambient temperature under an inert dry atmosι Ί phere (e.g., nitrogen or argon) in an inert anhydrous lower halohydrocarbon solvent such as, chloroform, 1,2-dichloroethane or methylene dichloride (most preferred). Other inert anhydrous organic solvents that may be employed include ethers such as ' I diethyl ether, dioxane, tetrahydrofuran (THF) or 1,2-dimethoxy- 9 ethane? and aromatic hydrocarbons such as, benzene, toluene and xylene. The foregoing reactions may be illustrated as follows: n (VI) . · Alternatively, the corresponding 2-loweralkylthiolactira ethers of formula (III-c) may be prepared by reaction of the lactam of formula (VI) with P„S_ according to the procedure of 2 b R. Gompper and W. Elser, Org. Syn., Coll. Vol. V, p.780-783, to yield the thiolactam of formula (via). Treatment of this 10 thiolactam With lowersIkylating agentsuch as methyliodide, methyl fluorosulfonate, dimethyl sulfate, methyl tosylate or methyl mesylate, yields the desired 2-loweralkylthiolactim ethers as the corresponding salts. Reaction of the thusderived loweralkylthiolactim ether salts with an appropriate guanidine of formula IV yields the corresponding salts of formula I. 44 -(CH9)n ι 2 Π -(CH ) n P2S5 lowersIkylating agent N I Ri (VI) ii I Ri (via) (I) (salt) It has been found that, under the aforementioned conditions of reacting the formula (Ill-b) lactam fluorosulfonates with' the formula (IV) guanidines, a side reaction may occur which gives rise to the following type of by-products .(ch2) n NR II N-C-NR.R. . CH, 4 5 J OSO2F which may be isolated by conventional recovery techniques.

Such salts are quaternary derivatives of formula (I) having antiseeretory and hypoglycemic activity.

The preferred method of making those compounds of formula (I), when R^ is hydrogen, is by reacting the free base form of (III), rather than the fluoborate or fluorosulfonate salt, with the heretofore described guanidine derivative (IV). Standard treatment of said salts of formula (III) with alkali, i” preferably in a halogenated hydrocarbon solvent such as methylene dichloride or chloroform, readily yields the free base (IX) which is then reacted with the desired guanidine . derivative (IV),; preferably in an anhydrous lower alkanol 5 solvent suck as,methanol, isopropanol, or tert-butanol, to yield the corresponding compounds of formula (I), which may exist in tautomeric form (X). Elevated temperatures up to reflux may be advantageously employed during the latter step as well as a stoichiometric excess of the free base (IX).

An alternative method of preparing the formula (I) compounds is by the interaction of the lactam (VI) with dimethyl sulfate (XI) to give the corresponding methosulfate salt of (III) according to the reaction conditions described by Bredereck et al., Chem. Ber. 96, 1350 (1963). The reaction is preferably carried out in an anhydrous inert organic solvent such as, an aromatic hydrocarbon, e.g., benzene, toluene or xylene, an ether, e.g., tetrahydrofuran or dioxane, or a halocarbon, e.g., 1,2-dichloroethane or chloroform. The so-obtained methosulfate salt (XII) is then reacted with the desired guani- 12 *4792 dine derivative (XV) as before, preferably at 25° to 100°C, to yield the corresponding methylsulfate salts of formula (I), which in turn may be transformed into the corresponding free, bases of formula (X) by treatment with alkali.

The free bases of formula (I) may also be obtained from methosulfate salt (XII) by reaction thereof with an alkali metal loweralkoxide, preferably sodium methoxide or sodium ethoxide in the corresponding lowerslkanol solvent, according to t:he reaction conditions described by H. Bredereck, et al, Chem.' Ber., 97,3081-3087 (1964), to yield the corresponding lactam acetal of formula (xiia). The lactam acetal, in turn, may be reacted with an appropriate guanidine of formula (3JV) to yield the free base of formula (I). The foregoing reaction schemes may be illustrated as follows: alkali metal lower alkoxide (IV)> (I)(free base) loweralkyl loweralkyl (Xiia) 4792 Another method of preparing the formula (I) compounds is by the interaction of the guanidine precursor (IV) with a chloride of formula (XIII) in an'anhydrous, aprotic solvent, such as, an ether, e.g., diethyl ether, dioxane or THF, a halohydrocarbon, e.g., chloroform, methylene dichloride or 1,2dichloroethane, and, preferably, an aromatic hydrocarbon, e.g., benzene, toluene or xylene. The chloride salts (XIII) are readily obtained by activation of the lactam (VI) with phosgene (C1C0C1) or thionyl chloride (SOClg) according to the directions of W. Jentzsch and M. Seefelder, Chem. Ber., 98, 274 (1965), with the evolution of COg or SOg, respectively. The foregoing reaction scheme may be illustrated as follows: C02T + ClCOGl -=> (or SOClg) (SOgf) -(CH ) n s (IV) Cl-»(!) N v (XIII) Instead of the aforementioned lactams (VI) starting materials, many of the subject compounds of formula (IJ may also be prepared from the 2-imino compounds of formula (XIV), wherein n, R^, Rg and Rg are as previously described. The 2-imino compounds (XIV). are for the most part described in the literature. Those that are not may be obtained according to the methods described in -Canadian Patent No. 950,464 (e.g. see Example 14 therein). These 2-imino precursors may be reacted with an isothiocyanate of formula (XV), wherein R is as previously described, and, preferably, other than 9-fluorenyl, in a reaction-inert organic - 14 solvent, e.g., benzene, CHgClg and chloroformat temperatures ranging from 0°C to ambient temperatures, for about 2 to 24 hours, in approximately equimolar amounts. The thio function (=S) in the thus-obtained thioureas (XVI), several of which are described intU S. Patent No. 3,717,648, is then transformed into an alkylthio function (-SR') by reacting (XVI) with an alkylating agent of the formula R'X, wherein R‘ is ethyl or, preferably, methyl, and X is iodide (preferably), tosylate, methosulfate, mesylate or fluorosulfonate. Typical solvents for such alkylations include ethers, preferably diethyl ether, tetrahydrofuran, or dioxane, lower ketones, e.g, acetone or 2butanone; halohydrocarbons and loweralkanols, preferably methylene dichloride and methanol, respectively. Methyl iodide as the alkylating agent in methanol is particularly suitable. Generally, equimolar to a large stoichiometric excess of the alkylating agent is used, the amount depending on the reactivity of the thiourea (XVI) or its solubility in the solvent employed. The alkylation reaction may be carried out at temperatures, ranging from ambient to reflux temperatures, or in appropriate sealed vessels at higher temperatures. The alkylthio compounds of formula (XVII) in acid addition (HX) salt form are then reacted at temperatures ranging from ambient to reflux or in appropriate sealed vessels at higher temperatures. The alkylthio compounds of formula (XVII), in aoid addition (HX) salt form are then reacted with an appropriate amine of the formula HNR^Rg, wherein R^ and Rg are as previously described except for Rg being phenyl or substituted phenyl, preferably in a lower alkanol solvent such as isopropanol and tert-butanol J, ' and generally at reflux temperatures, to yield the guanidine derivatives of formula (I), in similar acid addition form, which are readily obtained as the corresponding base form by conventional treatment with suitable alkali. The foregoing reactions may be illustrated as follows: (XIV) (XVI) (I) * salt (I) The isothiocyanates of formula (XV), many of which are known, may be prepared according to the extensive processes reported in the literature for making isothiocyanates. For example, they may be obtained by the methods described by M. Bogemann et al. in Methoden der Organische Chemie HoubenWeyl, Eugen Muller (Ed.), Georg Thieme Verlag (Publ.) -16-. 447fl3 Stuttgart, Germany, Vol. 9, page 867-884 (1955); Preparation des Isothiocyanates Aromatiques” by A. Rasschaert et al., Ind. Chim., Beige, 32 106 (1967); German Patent No. 1,300,559; J. Org. Chem., 36, 1549 (1971); U.S. Patents NOs. 2,395,455 and 3,304,167;. French Patent No. 1,528,249; A New Synthesis of Aliphatic Isothiocyanates Angew, Chem. internat. Ed., 6. 174 (1967); Bull. Chem. Soc. Japan, 48 2981 (1975); Tetrahydron, 29 691 (1973); Chem. Ber., 101, 1746 (1968); and J. Indian Chem. Soc , 52, 148 (1975).

In the foregoing reaction of (XVII) with the amine, HNR.R,, it is preferred to use a stoichiometric excess of the 4 5 latter, for example, in 1:1.05 to 1:2.0 molar ratios. If only a slight excess of the HNR^Rg amine is used, it may be advantageous to add a stoichiometric equivalent of a tertiary alkyl amine, e.g., Et^N, in order to enhance the rate of reaction. By-products, such as: NR H Η N—C—NRR may be formed during the course of the reaction. By standard techniques known in the art, such as, by fractional solubilization, such by-products can be separated from the desired formula (I) product.

Another method of preparing the formula (I) compounds from the 2-imino precursors of formula (XIV) is by the reaction of two molar equivalents of free base (XIV) with a compound of formula (XVIII)., wherein R^, R^ and R are as previously - 17 t47Q2 described. During the course of the reaction, an equivalent of the 2-imino precursor in salt form (XIX) is formed. For this reason, the reaction is preferably carried out in an aprotic solvent which preferentially dissolves the desired formula (I) product in base form allowing the ac: 3 addition salt (XIX) to precipitate. The two can then be easily separated by filtration and the latter reconverted to free base by conventional treatment with alkali and made available for re-use. Typical of such preferential solvents are. ethers, e.g., diethyl ether and THF, lower alkanones and esters, e.g., acetone, methyl ethyl ketone and ethyl acetate, aromatic hydrocarbons, e.g., benzene, toluene and xylene, acetonitrile and similar solvents. Diethyl ether is generally preferred. The foregoing reaction may be illustrated as follows: ‘4 5 NR II ci-c-nr4rs Et2° (XIX) The preparation of many varied guanidine derivatives has been extensively reported in the literature. Accordingly, the guanidine precursors of formula (IV) are readily obtainable by several available synthetic routes. For example', a thiourea - 18 ^4732 of formula (XX), wherein R is as previously described [prepared according to such methods as those described by R.L. Frank + P.V. Smith, Org. Syn. Coll. Vol. Ill, p. 737 (1955); A. Rasschaert. et al., Ind. Chim. Beige, 32. 106 (1967) ; G Barnikow + J. Bodeker, J. fflr prakt. chemie, 313, 1148 (1971); R.G. Neville + J, J. McGee, Org. Syn. 45, 69 (1965); C.P.

Joshua + K. N. Rajasekharan, Chem. + Ind. p. 750 (1974); and J. Chem. Soc. Transactions, p. 1702 (1924)], is converted to an alkylthio compound of formula (XXI) by alkylation of the former with the previously described R'X alkylating agent.

The thus-obtained alkylthio compound (XXI) is then reacted with an appropriate amine of the formula HNR R , except where 4 5 I R_ is phenyl or substituted phenyl, to give the guanidine derivative (XXII) in acid addition (HX) salt form which may then be converted to the corresponding base form (IV) by conventional treatment with alkali. To enhance the rate of reaction, a tertiary alkyl amine, e.g., Et^N, may be advantageously employed. The reaction conditions for the foregoing are the same as those previously described for converting the thiourea (XVI) to the alkylthio compound (XVII) to the final product (I). [See L. A. Kiselev et al., C.A., 86179t (1975)].

S SR1 || K'x I . hnr4r5 RNH-C-NH2 -> RN=c~NH2.HX -> (tautomeric) (XX) (XXI) nr4r5 alkali NR. ΚΙ 4 5 RN=C-NH2.HX -> RN=C-NH2 (tautomeric) (XXII) (IV) 44792 : A method of preparing the guanidines of formula (IV), wherein R is phenyl or substituted phenyl, R^ is hydrogen and Rg is phenyl or substituted phenyl, is by starting with an appropriate N,N‘ diarylthiourea of formula ArNHC(=S)NHAr1, wherein each of Ar andAr’ is phenyl· or substituted phenyl, which is reacted with ammonia according to the method described in J. Org. Chem. (O.S.S.R.), 2 (12), 2144, (1966) (English translation).

Another method of preparing the formula (IV) guanidines, preferably wherein R is the previously described alkyl, cycloalkyl, aralkyl, diphenylalkyl, phenyl and phenyl substituted with loweralkyl, loweralkoxy, halo and nitro, is by the method described by E. Kuhle, Angew. Chem. internat. Ed., 8, 24, 26, (1969) and references cited therein which involves the sequential displacement of chloride from an appropriate isocyanide dihalide (XXIII). The latter, the preparation of which is described by E Kuhle et al. in Angew Chem. internat. Ed., 6. 649- (1967), is reacted with the amine, HHR.Re, wherein R_ is other than phenyl or substituted phenyl, in the presence· of a trialkylamine, e.g. triethylamine, in a suitable reactioninert aprotic anhydrous solvent such as diethyl ether, a halohydrocarbon or an aromatic hydrocarbon, to give the monohalide compound (XXIV). Treatment of the reaction mixture with excess anhydrous ammonia', followed by treatment with dilute alkali, e.g. , an alkali- metal hydroxide or carbonate, yields the corresponding guanidine derivative (IV). - 20 44792 Cl RN=C-C1 + HNR^Rg + EtgN (XXIII) (XXIV) NR.R 1 4 5 RN=C-Cl + EtN.HCl nr4r | xs NH alkali RN=C-Cl --> (IV) (XXIV) An additional method of preparing formula (IV) guanidines, wherein R is phenyl or substituted phenyl, is by reaction of an appropriate aniline (XXV) with a cyanamide of formula (XXVI) to yield the guanidine salt (XXII) according to the methodology described by N.M. Golyshin et al. in British Patent Specification No. 1,341,245 and Chem. AbS. 79, 66O52f (1973), 80 95571a (1974) 82, 86179t (1975) and 68, 86760g (1968).

See also J. Diamond et al., U.S Patent No. 3,976,643 HCl alkali R-NH2 + NC-NR^Rg -> (XXII) -> (IV) (XXV) (XXVI) A further method of preparing formula (IV) guanidines, wherein R is phenyl or substituted phenyl, is according to the method of W. Abraham + G. Barnikow, Tetrahedron, 29, 691, 699 (1973), which describes the acidic hydrolysis of an appropriate 2-isothiocyanatoamidine of formula (XXVII), the latter being obtained from the interaction of the monohalide compound (XXIV) with ammonium thiocyanate NR.R. , 45 RN=C-C1 (XXIV) NH.SCN NR.R j 4 5 RN=C-NCS (XXVII) H+ HOH (XXII) + COS Still another method of preparing the formula (IV) guanidines, wherein R is as originally described, is according to the method of H.G. Viehe + Z. Janousek, Angew. Chem. internat Ed., 12 (10), 806 (1973), from the interaction of an appropriate dichlororaethyleneammonium salt of formula (XXVIII), except when WR^Rg is thiamorpholino-I-oxide, With an appropriate amine (XXV) to yield the corresponding monohalide compound of formula (XVIII) which is then treated with excess ammonia, followed by alkali, as before, to yield the desired guanidine derivative (IV). j I 4 5 xs NH- alkali I β θ I 3 RNHg + C1-C=NR4R5 Cl —RN=C-Cl -......--> ---> (IV) (XXV) (XXVIII) (XVIII) The compounds of formula-(I) and the acid addition and quaternary salts thereof possess valuable pharmacological properties, particularly as anti-secretory and hypoglycemic agents. The present invention includes within its scope a pharmaceutical composition which comprises at least one com15 pound of Formula I, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compounds of (I) and salts theraof have been found to possess anti-secretory activity by the following acute gastric fistula rat test. The anti-secretory activity of the compound to be tested is studied in female Sprague-Dawley rats after intraduodenal (i.d.) injection of the compound at doses generally ranging from 2.5-40 mg./kg. body weight. The rats are fasted 24 hours before testing and are given water ad libitum while being kept in individual cages. On the day of testing, the rats are weighed and are selected so that the 7a3 rats in each test have weights within a range of +20 g.

Surgery is carried out under light ether anesthesia.

As soon as the rat is anesthetized its teeth are removed, using a small pinch pliers. A mid-line incision is made on the abdomen about 1 1/2 cm in length and the stomach and duodenum are exposed. If at this point, the stomach is filled with food or fecal material, the rat is discarded. Using 4-0 suture, a purse string stitch is placed on the fundic portion of the stomach taking care not to pierce any blood vessels in the area. A small nick is made into the stomach in the center of the purse string, and a cannula, consisting of a small vinyl tube with a flange on one end, is put into the stomach and the purse string stitch is closed tightly around the flange. Immediately following this, the test compound is administered I.D. in a volume of 0.5 ml per 100 gm rat. Three rats are generally used for each drug dose tested. Control rats receive the test vehicle, usually 0.5% aqueous methyl cellulose.

After administration of the test compound, the abdominal wall and skin are closed simultaneously with three to four 18 mm wound clips and a collecting tube is placed on the cannula. Each rat is then placed in a box in which a longitudinal slit has been made to allow the cannula to hang freely and to allow the rat to move about unencumbered. After the rat is allowed to stabilize for 30 minutes, the collection tube on the cannula is discarded and replaced with a clean tube to receive the gastric juice. Collections are made at one hour. At the end of the study, the cannula is removed as the rat is sacrificed.

The sample of gastric contents collected is drained into ι - 23 .4192 ? a centrifuge tube and centrifuged to pack down the sediment. Volumes are read and a 1 ml aliquot of the supernatant is put into a beaker containing 10 ml distilled H^O and is titrated to pH7 using 0.01N NaOH. Results are determined for Volume, Titratable Acid, and Total Acid Output where Volume = total ;-ml. of gastric-juice minus sediment; Titrable Acid (milli- equivalents/l) = amount of 0.01N NaOH needed to titrate the acid to pH7; and Total Acid Output = Titratable Acid X Volume.

Results are reported in % Inhibition vs Controls and a minimum of 5% Inhibition indicates anti-secretory activity.

In addition, the subject compounds (I) and salts thereof have been found possess blood sugar lowering activity (i.e. hypoglycemic properties) as demonstrated in the following rat glucose tolerance test, particularly those of formula (II).

The rat glucose tolerance test is a standard and extremely sensitive procedure used'in the diagnosis of diabetes and hypoglycemic disease states.

Male Sprague-Dawley rats (Charles River 184-250 gm) are given water .ad libitum and fasted 24 hours prior to the experi20 ment. Serial blood samples (0.1 ml) are obtained from the tail-without anesthesia at O, 30, 60, 90, 120, 150 and 180 minutes after.oral administration of lg glucose/kg body weight in 1 ml water. Specimens of blood are immediately deproteinLzed with aqueous solutions of Ba(0H)g and ZnSO^ and glucose levels are determined using the glucose oxidase assay described by L.R. Cawley et al., Ultra Micro Chemical Analysis of Blood Glucose with Glucose Oxidase, Amer. J. Clin. Path., 32, 195 (1959). - 24 -Two to five rats are used for each test and control group. Test Compounds (1-200 mg/kg s.c. or i.p.) are administered suspended in 0.5 or 1.0 ml., but preferably the former, of 0.5-1.0% methylcellulose. Controls are given an equal amount of vehicle subcutaneously. The blood glucose values at each time point are expressed in terms of mg % (mg glucose/100 ml of blood). The mean glucose values of the controls are compared statistically by the Student's t-Test to the means of the experimental group at each of the corres10 ponding time points. If the compound lowers the blood glucose significantly at. any time at a 95% confidence limit, the compound is considered to have hypoglycemic activity.

Examples 1 to 13 and 23 relate to the preparation of intermediate derivatives.

EXAMPLE X A.· N-(l-Methyl-2-pyrrolidinylidene)-N1-phenylthiourea; To 6.73 g (0.05 mole)' of 2-imino-l-methyl-pyrrolidine hydrochloride, as a stirring suspension in benzene, is added 5 ml of 50% aqueous NaOH solution. . After stirring about 2 minutes, the organic layer-is decanted onto K2COg (anhyd.) and the extraction is repeated twice with fresh benzene. The combined extracts, after drying, are quickly filtered (diatomaceous earth pad) with suction, minimizing air contact to avoid carbonate salt formation, and 6.76 g.(0.05 mole) of phenyl10 isothiocyanate is added in one portion. After stirring for three hours, the resulting solid is collected. A second crop is obtained from the mother liquor. Recrystallization from , I ethyl acetate gives pure product; N-(i-methyl-2-pyrrolidinylidene)-Ν'-phenylthiourea, m.p. 142-143.5°c.

·. B. Methyl, N-(l-methyl-2-pyrroiidinylidene)“Nl-phenylcarbamimidothioate Hydroiodide; To a solution of 34.86 g (0.15 mole) of N-(lf-metihyl-2-pyrrolidinylidene)-N1-phenylthiourea in 500 ml of acetone is added 21.3 g (0.15 mole) of iodomethane in acetone. The solution is,refluxed for 1/2 hour and allowed to stand at room temperature for an additional hour. A solid, . crystallizes upon cooling (ice bath). Following recrystallization from methanol-isopropanol, pure methyl K-(l-methyl-2pyrrolidinylidene)-N*-phenylcarbamimidothioate hydroiodide is obtained; m.p. 145-147?C.

-J S 44782 C. Treatment of the compound of Example I-A in either lover alkanol solvents, acetone, or lower halohydrocarbons with either methyl £-toluenesulfonate, dimethyl sulfate, •uethyi fluorosulfonate, trimethyloxonium fluoborate or methyl methanesulfonate affords the methylthio compound of Example I-B as the corresponding respective salt.

D. N-(l-Methyl-2-pyrrolidlnylidene)-N1-phenyl-1pyrrolidinecarboximidamide Hydroiodide; A solution of 15.02 g (0.04 mole) of the compound of Example I-B and 4.31 g (0.06 mole) of 99% pyrrolidine in 100 ml of isopropanol is refluxed for twenty-four hours. A solid crystallizes upon cooling (ice). The crystals are collection by filtration and the mother liquor set aside (see Example XXVI).

After recrystallization. of the crystals from isopropanol and methanol-ether, pure N-(l-methyl-2-pyrrolidinylidene)N1-phenyl-l-pyrrolidinecarboximidamide hydroiodide is obtained; m.p. 206-208°C. .

EXAMPLE II In accordance with Canadian Patent No. 950,464, there ' are obtained the following acid addition salts of the 2-imino compounds of formula (XIV): a. 2-imina-l-methyl-5-phenylpyrrolidine fluoborate, m.p. 128-31°C; 5 b. 2-imino-l-methyl-pyrrolidine’fluoborate, m.p, 109-ll°C; c. 2-imino-l-ethyl-pyrrolidine hydrochloride, m.p. 181-85°C; d. 2-iminO-l-n-butyl-pyrrolidine cyclohexanesulfamate, m.p. 110114.5°C;' e. 2-imino-l-benzyl-pyrrolidine fluoborate, m.p. 112-114°C; £. 2-imino-l,5-dimethyl-pyrrolidine fluoborate, m.p. 100-102°C; g. ,2-imino-l-methyI-piperidine hydrochloride; and h. hexahydro-2-imino-l-methyl-lH-azepine cyclohexanesulfamate, _m.p. 143-45°C. . ’ i. l-hydroxyethyl-2-iminopyrrolidine cyclohexanesulfamate, m.p. 105-108 °C. .

Each of· the foregoing salts is converted to the free base form by treatment with 50% NaOH as shown in Example I-A. «47a2 EXAMPLE III By following the procedure described by J. C. Jochims & A. Seeliger, Angew. Chem. internat. Ed., £ (2), 174 (1967) for making isothiocyanates, the following are obtained: a, 1- and 2-(2,3,3a,4,5,6,7,7a-octahydro-4,7-methanoindanyl)isothiocyanates; b. 1,1-Dimethylphenethyl isothiocyanate; c. Ι-α-Phenethyl -isothiocyanate; d. d-a-Phenethyl isothiocyanate; e. 1-Benzylcyclopentyl isothiocyanate; f. 7-(Bicyclo[4.2.0]octa-1,3,5-trienyl)isothiocyanate; g. 1-AdamantyImethyl isothiocyanate; h. 2-Adamantyl isothiocyanate; • i. trans-2-Phenylcyclopentyl isothiocyanate; j. cis-2-Phenylcyclopentyl isothiocyanate; . . k. trans-2-Cyclohexylcyclopentyl isothiocyanate; l. cls-2-Cyclohexylcyclopentyl isothiocyanate; and m. cis-2-Phenylcycloheptyl isothiocyanate.

- EXAMPLE IV Sy-following the procedure of Example I-A, except that an equivalent amount of an appropriate 2-imino compound obtained from Example XI is used as starting material in.reaction with an equivalent amount of ar. appropriate isothiocyanate there are . obtained, as respective products, the following thioureas of formula (XVI): a. N-2- (hexahydro-lH-l-methyl-azapinylidene-N' -phenylthiourea, m.p. 157-59°C; . b« N-l-methy1-2-pyrrolidinylidene-N'-diphenylmethylthiourea, 10 - m.p. 112-114°C (polymorph), 119-12Q°C; C. N-l-methy1-2-pyrrolidinylidene-N1-p-nitrophenylthiourea,. m.p. 179-180.5°C (dec.); - d. N-l-methyl-5-phenyl-2-pyrrolidinylidene-N1-phenylthiourea, m.p. 135-140°e? e. N-l-methy1-2-pyrrolidinylidene-N'-p-fluorophenylthiourea, . m.p. A52-54°Ci f. N-l-methvl-2-pyrrolidinylidene-N'-benzylthiourea • m.p'. (71) 74-31°C; g. N-l-methyl-2-pyrrolidinylidene-N'-2-naphthylthiourea - m.p. 159-162°C (dec.)’; h. N-l-methyl-2-pyrrolidinylidene-N'-cyclohexyithiourea . m.p. 88-93°C; i. N-l-methyl-2-pyrrolidinylidene-N'-p-methoxyphenylthiourea, ·-. m.p. (149) 150-152°C (dec.); j. N-l-methyl-2- k. N-l-methyl-2-pyrrolidinylidene-N'-2,6-dimethylphenylthiourea, m.p. (164) 165-68°C? l. N-l-methy1-2-pyrrolidinylidene-N'-1,1,3,3-tetramethylbutyl30 thiourea; m.p, 115^116.5°C. m. N-l-methyl-2-pvrrolidinylidene-N,-l-adamantylthiourea, m.p. 150-52°C; n. N-l-ethyl-2-pyrrolidinylidene-N'-phenylthiourea, m.p. 158°C; o. N-l-ethy1-2-pyrrolidinylidene-N'-p-methoxvphenylthiourea, . m.p. 128-30°C; and · p. N-l-methyl-2-piperidinylidene-N'-phenylthiourea, m.p. 132-34°C. 44702 EXAMPLE V The S-methylation procedure of Example I-B is followed, utilizing the indicated solvent with the thiourea precursor of Example IV as the starting material to be methylated, to yield the following methylthio hydroiodide salts of formula (XVII): Example IV Precursor Solvent S-Me’HI (m.p.) a CH2C12 157-59°C b acetone 122-23°C c MeOH — d MeOH 150-52°C e MeOH/acetone 104-105°C f acetone 123-25°C g ch2ci2 glass h ch2ci2 (oil) i ch2ci2 124-25°C ' j ch2ci2 16568°C k ch2ci2 189-92°C (dec.) 1 MeOH (oil) Hl . MeOH 1'45-48°C n οη2οι2 ; 117-19°C o acetone (oil) P acetone 164-S5°C EXAMPLE VI The procedure of Example I-D is . followed in preparing the guanidine derivatives of formula (I) as the free base or acid addition salt, except that an appropriate methylthio hydroiodide precursor obtained from ExamplesI-B and V and an appropriate amine of the formula HNR4R5 are used as starting materials in a 1:1.5 to 1:3 molar ratio, respective- ly, in refluxing isopropanol or, preferably, tert-butanol to yield the ·respective formula (I) product as the correspond. ing hydroiodide salt, which is then isolated as such, or con10 verted to .the corresponding base form by conventional treatment with, aqueous alkali, or reconverted to another acid addition salt by reaction of the base form with the indicated acid.

In addition, the formula (IV) guanidines may be formed as by-products and may be isolated from the reaction mixture, e.g., by selective solubilization or fractional crystallization techniques, either as the free base or acid addition salt form.

S-Me-HI Precursor -NR4R5 Formula (I) Product Form m.p. (°C) Example I-B -Ό HI 1S3-200 it « II 185-188.5 M II -ΝβΝ-Ph base 131-33 .., * >1 M -®C° HI. (163-4) 171-73 II tl -ΝΗ-θ base • 82-84 II II -N.(Me)CH2Ph HI 180-82 11 11 . -N^N-Me HI 161-161.5 Me »· II II -Q HI (193) 197-199 dec 'me II II Me Me 2 HI 269-270 dec 479s S-Me-HI Precursor -NR4R5 Formula Product (I) Form m.p. (°C) Example v-a -<3 HI 192-93 ii V-b it It . 218-20 tl v-a tl II 201-03 tl V-e II tt 190-92 n V-f n II (165) 167-71 II V-g tt II 187-89 it V-h It II 203-04 II V-i II II 142-44 It V-j ti II 183-85 tl V-l 11 HC1O4 154-55 II V-m it EI 171-73 11 V-n it II 142-43 tl V-o II It 164-66 II V-p It If 151-53 EXAMPLE VII A. This example illustrates ^the preparation of N-benzoyl thioureas according to the methods of R. I. Frank & Ρ. V.

Smith, Org. Synth. Coll. Vol. Ill, p. 735 (1955) [see also G. Barnikow & J. B. Bodeker, j. prakt. Chemie, 313, 1148 (1971)].

Accordingly, the following benzoylthioureas are prepared: I a. N-benzoyl-N'-3,4-dimethoxyphenylthiourea, m.p. 133-34°C; b. N-benzoyl-N'-p-benzyloxvphenylthiourea, m.p. (120) 132-37°C. c. N-benzoyl-N'-(4-methylthiophenyl) thiourea, m.p.l60-161QC.

B. Substituting' carbethOxyisothiocyanate for benzoyl isothiocyanate oneobtaihs M-carbethoxy-N'-(3,4-methylenediOxyphenyl) thiourea, m.p. (137) 146-148°C. 34 EXAMPLE VIII This example illustrates the hydrolysis of appropriate benzoylthioureas and carbethoxythioureas to the thioureas of formula (XX) according to the methodology described by R. L. Frank & P.V. Smith, Org. Syn. Coll. Vol. Ill, p. 735 (1955).

A. 3,4-Dimethoxyphenylthiourea. To a one liter beaker containing 95.85 g. (0.302 mol) of N-benzoyl-N’-3,4-dimethoxyphenylthiourea is added 230 ml of 10-12% NaOH solution and 60 ml of Η^ο. The mixture is heated to temperatures of about 60-80° for 5-10 mins, until hydrolysis is completed.

Filtration of the hot solid, followed by washing with water until the filtrate becomes neutral, then washing with MeOH and drying gives the product, 3,4-dimethoxyphenylthiourea; m.p. 234-242°c (dec.).

B. p-Benzyloxyphenylthiourea; The foregoing procedure of Example VIII-A is repeated, except that an equivalent amount of N-benzoyl-N1-p-benzyloxyphenylthiourea is used as the material to be hydrolyzed, to yield p-benzyloxyphenylthiourea as the product, m.p. 193-95°C.

C. 4-Methylthiophenylthiourea, m.p. (187) 190-191°C, is similarly obtained.

D. 3,4-Methylenedioxyphenylthiourea, m.p. 207-209°C, Alkaline hydrolysis of N-carbethoxy-N'-(3,4-methylenedioxyphenyl) thiourea under conditions described above followed by neutralization with mineral acid (Caution: vigorous COg evolution) affords 3,4-methylenedioxyphenylthiourea, m.p. 207-209°C. .4** a* EXAMPLE IX .

This example illustrates the preparation of formula (XX) thioureas according to the method of C. P. Joshua & K. N. Rajasekharan, Chem, & Ind., p. 750 (1974).

A. 4-n-'Butylphenyl thiourea: To 100 ml of hot HCl (18%) is added 90.2 g (0.605 mole) of p-n-butylaniline (97%) followed by 46.1 g (0.605 mole) of NH^SCK. The resultant mixture is heated under reflux for about one hour and then poured over crushed ice to yield crystals which are recrystallized from ethyl acetate to give the pure product, 4-n-butylphenylthiourea, m.p. 123-25°C.

B'. 3,4-Methylenedioxyphenylthiourea, m.p. 208-210°C.

C. 4-Methoxyphenylthiourea, m.p. 207-210°C. 36/ EXAMPLE X This example, which illustrates another method of making the formula (XX) thioureas, involves the interaction of excess ammonia v/ith an appropriate isothiocyanate, generally in an ethereal type solvent.

A. 1-(exo-2-Norbornyl)thiourea: exo-2-Norbornylisothiocyanate [prepared by the method of Diveley et al/, J.

Org. Chem., 34, 616 (1969)] (27.17 g., 0.178 mole) in 200 ml dry monoglyme is treated with ammonia gas for 5 hrs. The mixture is let stand overnight. The product is separated by filtration and washed with ether to afford a solid, l-(exo2-norbornyl)thiourea, m.p. 181-1S3°C. Β. N-(9-Flu6renyl)-thiourea: To 16.52 g (0.074 mole) of 9-fluorenylisothiocyanate in ether is added excess anhydrous NHj with cooling. The reaction mixture is capped and allowed o to stand overnight at 0 C. Filtration gives the product, 15-(9fluorenyl)-thiourea, m.p. (153°) 182-189°C.

C. By following the foregoing procedures of this example, except that an equivalent quantity of an appropriate isothiocyanate is reacted with excess ammonia, the following are obtained as respective products: 2- (Bicyclo[2.2.2.]octyl)thiourea; endo-2-(Bicyclo[3.2.1.]octyl)thiourea; anti - 7 -norbor neny ltr.i our ea; lr and 2-(2,3,3a,4,5,6,7,7a-octahydro-4,7-methanoindanyl)thioureas; 3- (2,3,6,6a-Tetrahydro-lH-l,3a-ethanopentalenyl)thiourea; -(3a,4,5,6,7,7a-hexahydro-4,7-methanoindenyl) thiourea; ,.1-Dimethylphenethylthiourea; d-a-phenethylthiourea; Ι-α-phenethylthiourea; l-BenzylcycIopehtylthiourea; 1- Bicyclo [.4.2.0.] octa-1,3,5-trienylthiourea ; I-Adamantyimethylthicurea; 2- Adamantylthiourea; . eis-2-Phenylcyclogen.tylthiourea ; cis-2-Phenylcycloheptylthiourea and e is-2-cyclohexyIcyclopentylthiourea.

EXAMPLE -XI .

A. Methyl. N-(9-fluoranyl)carbamimidothioate Hydroiodide.s To 7.85 g. (0.033 mole) of N-(9-fluorenyl)thiourea in 200 ml acetone is. added 4.68 g (0.033 mole) of methyl iodide. The mixture is allowed to stand at room temperature for about 4 -hours. Ether (400 ml) is added and the mixture allowed to stand overnight, affording the crystalline product, methyl ΪΓ-(9-fluorenyl)carbamimidothioate hydroiodide, which is filtered Off;;m.p. (208) 212-14°C. . B, The foregoing S-methylation procedure of Example XI-A is. fdlloWed, except that an equivalent quantity of an appropriate thiourea is reacted-with methyl iodide in the indicated molar ratios,.respectively, and using the indicated solvent reaction medium to yield the following products of formula -(XXI). as the hydroiodide salt: SMe I 1 RN=C-NH -HI 2 Ratio of (XXI) R Solvent Reactants m.p. (°C) exo-2-norbornyl acetone 1:1.1 (oil) g-n-Bu-Ph acetone I 1:1 77-79 9-fluorenyl acetone 1:1 (201) 212-14 1-naphthyl CH2Cl2-MeOH (4 :1) 1:1 191-192 m-CP3-Ph acetone - 1:1 120-22 m-MePh acetone 1:1.5 145-50 3,4-diOMe-Ph MeOH 1:4 186-193 g-PhCHjO-Ph acetone 1:2.2 (195) 198-202 χ'θχ 3,4-CH, },Ph MeOH 1:1 138-138.5 3-OMePh acetone 1:1.5 119-123 3-Cl-Ph MeOH 1:1.1 (120) 125-129 4-NOj-Ph MeOH 1:2 190-197 dec. 4-OMePh acetone 1:1.1 161-164 4-SMePh acetone 1:1 158-160 4-NMe2-Ph MeOH 1:1 ,166-168 3-Pyridyl acetone 1:1 98-100 (free base) 4-Me Ph - MeOH ' 1:1 129-130.5 . 39 ' C. Sy repeating'the foregoing S-methylation procedure . of Example XI-A,. but using an equivalent amount of each thiourea obtained from Example.X-C in methanol as the reaction solvent and with a slight stoichiometric excess of methyl iodide, the corresponding carbamimidothioate hydroiodides of formula (XXI) are obtained. 40 EXAMPLE XII Α· Ν- (4-Tolyl) -l-pyrrolidinecarboximidamide Hydroiodide: 4-Tolylthiourea (33.2 g., 0.2 mole) in 200 ml. acetone is heated under reflux for 3 hrs. with methyliodide (31.4 g., 0.221 mole). Solvent is removed in vacuo and the resulting 2-methyl-l-(4-tolyl)-2-thiopseudourea hydroiodide dissolved in 200 ml. tert-butanol. Pyrrolidine (2S.4 g., 0.4 mole) is added and the mixture heated at reflux for 18 hrs. The reaction mixture is cooled, diluted with ether and the resulting solid separated. Recrystallization from acetone-ether affords N-(4-tolyl)-1—pyrrolidineoarboximidamide hydroiodide, m.p, 166-168°C. Conventional treatment of the salt in CHjOl^ with aqueous (10-20%) NaOH affords the corresponding free base. Β. H-2,6-Dichlorophenyl-l-pyrrolidinecarboximidamide Hydrochloride: A mixture' of 14.52 g (0.04 mol) of methyl N-2,6-diohlorophenyloarbamimidothioate hydroiodide and 5.69 g (0.08 mol) of dry pyrrolidine in 30 ml of t-BuOH is heated under reflux for 3 days. The solvent is removed in vacuo and the resultant non-crystalline hydroiodide salt is converted to the free base in CH2C12 with cold- 20% NaOH followed by drying (I^CO-j), solvent removal, and conversion . of the base to the HCl salt in isopropanoi using anhydrous HCl. Recrystallization from isopropanoi, using sufficient MeOH to effect -solution, gives the pure product, N-2,6-dichlorophenyl1-pyrrolidinecarboximidamide hydrochloride, m.p. 292-295°C.

C. The foregoing procedures of Examples XII-A and B are followed, except that an equivalent amount of an appropriate methylthio hvdroiodide of formula (XXI) is reacted with an appropriate amine (HNR^Rg) in the indicated molar ratio, respectively, with.or without an additional equivalent of Et^N as indicated, in.refluxing tert-butanol to yield the following respective. guanidines , isolated either as the free hase or as the indicated aoid addition salt: nr4r5 - RN’C-UHg' HX R -NR4R5 HX Molar Ratio- Added Base m.p. (°C) Ph /°x 3,4-ch; .Ph O -O'. 'HBr -HI 1:1.1 1:2 . Et3N 203.-205 ' 171-172.5 £-n-C4H9-Ph -NEt2;- fumarate . 1:2 - 96-98 c-OH-Ph a. -c - HI 1:2 - 216-218 m-Me-Ph ' - -N (Me) -Q . cyclamate 1:1.06 Et3N 170-172 £-Me-Ph o. ·. HI 1:2 - 166-168 m-Cl-Ph - -O> base 1:2 - 143.5-145.5 2,6-diCl-Ph -ΰ . HCl 1:2 - '292-295 Ph /“Λ -N^O HI 1:2 - 175-177 ' Ph o hn°3 1:2 - 139-141 £-NO2-Ph . -c . . El . 1:2 240-242 (dec.) (Ph)2CH -*G° base 1:2 122-124 Ph - -N (Me)-(j HI 1:1.3 EtgN 149-152 £-Me-Ph HI 1:2 - 166-168 (Ph)2ch -»0 . . HI 1:2 - 205-206 exo-2-notbornyl - • HI 1:2 - 160-163 u -O HI. 1:2 - 198-199.5. Ph. -•a HCl 1:2 - ' 181-184 3,4-diMeO-Ph -e HI 1:2 - 221-222 m-CFj'-Ph -N(Me)’.-Q fumarate 1:1.3 EtgN 150-153 1-naphthyl - -N (Me) -\ / base 1:2 - 132-133 11 -NEt2 - .fumarate t 1:4 - 208-210 (dec.) 9-fluorenyl -e HI 1:2 - 247-249 (dec.) 1-naphthyl -«a HI 1:2 - 209-211 2,6-diMe-Ph HI 1:2 191-192 R 4-PhCH2O-Ph 3- OMe-Ph 4- OMe-Ph 4-OMe-Ph 4-SMe-Ph 4-NMe2Ph 4-NMe2Pft Ph 3- Pyridyl 3,4-CH- Ph 4- Me-Ph 4-Me-Ph’ 4-Me-Ph 3-Me-Ph 3-OMe-Ph 3-Me-Ph 3-OMe-Ph -NR.R.' 4 5 ΗΧ Molar Ratio Added Base m.p. (Ό tosylate 1:2.1 - 187-190 O fumarate 1:2 - 187-189 Ν(Μβ)-θ base 1:2 - 120-122 Ν(Η)-0Η?-θ base 1:2 - 134-135 -Ρθ HI 1:1.1 Et.N(l) 174-175.5 3 -ο base 1:2 - (111)117-119 -ο 'S , ,Μδ -Ρνη HCl 2 HI 1:2.4 - 206-207 dec. 266 dec.s rp -Ν Ό base 1:2.1 188-190 \—/ -Ν (Μβ)-θ base 1:2 - 121.5-123 Γ~\ -ν ;ο \_( . HI 1:2 - 197-204 -Q base 1:1.2 Efe3N(l) 119-120 -ο HOAc - - 119-123 polymo (133)134-137 -Ps base 1:1 Et.N(l) 105 3 -N(Me)-Q base 1:2.6 Et3N{2.6) 93-95 Ό' HI 1:2 - (160)168-191 >—V -N^S HI 1:1,2. Et N(l) (188)189-192 ., S3. Each of the foregoing acid addition salts obtained in Example XII-C is converted to. the corresponding free base by conventional treatment with alkali.

EXAMPLE XIII .. ' N-Phenyl-l-pyrrolidinecarboxintidamide Hydrochloride? To 1.74 g (0.01 mole) of phenyl isocyanide dichloride. is added 0.71 g (0.01 mole)of pyrrolidine and 1.01 g (0.01 mole) of triethylamine underN., in dry ether with stirring and cooling. Th*e resulting mixture is allowed to stir for 1/2 hr and the resultant Et^N-HCl is filtered.

The filtrate is added to a saturated solution of anhydrous NH3 in isopropanol. The resulting NH^Cl is filtered and the filtrate is concentrated in vacuo to remove excess ammonia, followed by the addition of dry HCl resulting in crystalline product, N-phenyl-l-pyrrolidinecarboximida15 mide hydrochloride, m.p.· 181-84°C after crystallization from ..methanol-isopropanol.

EXAMPLE XIV N-(l-Methyl-2-pyrrolidinylidene)-N1-phenyl-l-pyrrolidinecarboximidamide L-(+)-Tartrates TO 1.84 g (0.013 mole) of boron trifluoride etherate in Et^O (anhydrous) under N2 is added 1.02 g (0.0'il mole) of epichlorohydrin with rapid stirring for 3 hrs. The resulting crystalline triethyloxonium fluoborate is washed with fresh anhydrous ether by decantation under N2. The crystals are dissolved in dry CH.2cl2. To • the solution is added 1109 g (0.011 Mole) of l-methyl-2-pyrolidinone and the mixture is stirred for 2 hrs. To. the resulting solution is added 0.01 mole of N-phenyl-l-pyrroli' dinecarboximidamide with cooling in an ice-water bath. The 4 4 73^. reaction mixture is allowed to stir overnight (ca. 16 hrs). The mixture is taken to dryness in vacuo and then diluted with ether affording crude crystalline salt of N-(lmethyl-2-pyrrolidinylidene)-Ν'-phenyl-l-pyrrolidinecarboximidamide.

The crystals are recrystallized from acetone to, give pure fluoborate salt); m.p. 164-166°C. The fluoborate salt is converted to the free base in CH2C12 with NaOH (20%) in ice. The organic layer is dried over anhydrous K^COj, then filtered and taken to dryness in vacuo affording the free base. To the free base in MeOH is added an equimolar amount of L-(+)-tartaric acid. The resulting solution is concentrated while adding isopropanol until substantially all MeOH has evaporated off affording the tartrate salt upon cooling. Recrystallization from isopropanol with a small amount of MeOH affords the pure product, N-(l-methyl-2-pyrrolidinylidene)-N’-phenyl-lpyrrolidinecarboximidamide L-(+)-tartrate, m.p. 153.5-156°C.

EXAMPLE XV By following the procedure of Example XIV, except that an appropriate lactam fluoborate of formula (ma) is reacted with an appropriate guanidine of formula (IV) in the molar ratio indicated', respectively, the following compounds of formula (I) are obtained and isolated as either free base or the indicated acid,addition salt: N e2' /LbN—C—NR4R5 R. '1 4793 Hi—'ΗΗ‘h-'WHH Τ γ 1 Y A %. g g 2 g g g g 5 3£- g I g £ g I B ’g· ·? ” - '3· nF Isa 1« ϊ nor J “-sr i? *ξ\ mffifflccaaffiffiffiffiffitaffiSffiffi CO cr tr (D InF ' '£ weFteKwaswBaBKaKHffiSsw Hw tr *4 ' ' kF MWAWJA Η H t4HOO Ht4 l4H14 RK>HH t4 R Vi CO Η R H Pi S’ £ $ ε £» R . s g t4 14 o. R cn t4 p Ϊ4 Co CO co t4 CO I Ϊ φ γ I R ί—1 w R 14 CO O to CO t4 cn •4 14 & CO σ ω β) Hi n SSBBSh e R P CO σ» cn p t4 as kUCocotncncntninco I I I I I I I I I t4HN>RRRpt4p Ο co ρ σ. tn co oo p ~ «4 Ο Ο σ» *4 «4 *J σ «4 *fc. oi σι τ 7 P t4 SCO w co O 478S. ω - UJ UJ UJ UJ UJ UJ NJ NJ NJ NJ NJ NJ NJ NJ NJ NJ P P es ' U1 UJ NJ P © SO CO © tn db. UJ NJ © © CO P Μ P P P P P P P P P P P P P UJ UJ UJ o UJ * η 1 A di £>> UJ 1 >> IS IS o § 1 I 1 1 I h3 1 I 1 o 3 §*< z cn o o O sr 3 2 x?\ 0 o 3 3 3 3 3 o σ n> *T3 ffi P 0 Φ fi) Φ fi) sc 3 hi kJ O OB 2 sr w ct sr NJ hi ST hi sr *3 sr hi sr NJ O φ *—» Sr * w UJ** &P sr I NJ B Lj »0 hi sr £ 0 sr sr B, 3 Is 3 3 3 3 j2 3 3 3 3 3 3 3 . 3 0 l fi) fi> fi> Φ 0 0 φ 0 fi> fi) ro . ro Φ O ro ro ro ro p NJ p 1—i It 13 [SS I 1 Ω 2 Ω Ω £>. w hi uj so sr T3 w S' S' a a w <1 BB'BBBBBBBBBSEBB tompound R1 r- R, NR,R_ - Molar Ratio Form of No. n R z - 4 b (jn) ; (iv) Product m.p. (°C) .EXAMPLE XVI Ν-(2,6-Dimethylphenyl)-Ν'-(l-methyl-2-pyrrolidinylidene)1- pyrrolldinecarboxiniidamide Fumarate; To a solution of 3.47 g (0.035 mole) of dry 1-methyl-2-pyrrolidinone in dry CH2C12 under dry N2 is added 3.99 g (0.035 mol) of methyl fluorosulfonate.

After 2 hrs., -a solution of 6.52 g (0.03 mole) of N-(2,6-dimethylphenyl)-1-pyrrolidinecarboximidamide free base in dry CH2C12 is added at room temperature with stirring in one portion. After stirring overnight at ambient temperature, the reaction mixture is basified with excess cold NaOH (2 OS). The organic 10 layer is.separated and the aqueous phase is extracted with ’2 x 50 ml of fresh CH2C12- The combined organic extracts, after drying over anhydrous K2CO3, are filtered and the solvent removed in vacuo. The residual oil is dissolved in ether and the. solution filtered through diatomaceous earth. Treat15 ment of the filtrate with a hot solution of fumaric acid in isopropanol to neutrality gives the product as the fumarate salt. Recrystallizations from isopropanol (filtering hot) gives the pure product, N-(2,β-dimethylphenyl)-Ν'-(1-methyl2- pyrrolidinylidene)τ1-pyrrolidinecarboximidamide fumarate, ' m.p. 182-84°C (slight dec.). 4 4 732EXAMPLE XVII The procedure of Example XVI is repeated, except that an appropriate guanidine of formula .-(IV) is substituted for the N-(2,6-dimethylphenyl) -1-pyrrolidineoarboximidamide used therein to react with the appropriate compound of formula (Illb) in the molar ratio indicated, to yield the following respective products of formula (I), which are obtained and isolated as either free base or the indicated acid addition salts il ω w ω U) Ui 1 I 1 J I I i S- O S o s Τ’ 2 n> 2 0 2 fi) Θ CD v ro >0 (0 ’ hJ *0 5Γ : v S'- Π3 S’ sr sr S' sr •C* Π ΙΑ ο ° δ Vi S' a S' w - Ρα σν ι I 3 Cl o H· to η ι w ·σ. I S' s* H I s » Ό S' (T S' H V S' Ό S' iii ) ι ι QOOiQOOW ά V 0 « a - a t ^3.

C_j ξ o C J ro a τη σ fo t S' S (5 ro g P p t - O t 1 o 52 ffl w Ni O O a 11 ϊ o n • tc . a NJ w s (5 s ro s (D 2 ro ro ro ro _ - P P P P P « • - P P P P « » • ' -P P • • • • Ni Ni - Ni -4 ·. Ni Ni NJ P P- P P Ni ·· ·· w P P P P P P P H P ·· -M P o to n o 0 .c s 0, IS) SI £> W •Ul I» Η P W Q> crh w .< Jtf tr — p W 0 < Hl 'C s fl) H & ft (0 Hl s fl) H fl) ft (0 Hi I s H ’fl) $ fc* I co Ni.

O Hi g fl) H fl) ft (0 Hi fl) H fl) ft fi) I ft fl) H ft io ' tr & w A tr &i w (0 H Hifi fl) H fl) ft CO H κ o 0 H £l· 3 β Ω 0 ft Hi ;p H λ- • Oi P P NJ Ρ , P w P -P P w P P Ni OS co 1 NJ Ul Oi Ό 1 co· Ul U) P - NJ in P © CO Oi O Jl· o GJ vo w Ul •r Jl· J I I 1 1 1 1 I NJ P w . l£fc H* u> H W- H P P w P ci 03 *-* / Ni Ol Ci Ό -4 co Ut P NJ tfl· Cl ;p Ni O- co P Λ. Ni Ul P Cl· Cl a 03 Cl· Cl· -£i · Cl· Ul Ul 8 l w fi) Ω 8 8 ro a -· T . ui 1 P P U) O I P CO co |L VO p EXAMPLE XVIII This example illustrates methods of preparing the quaternary salts of the formula (I) compounds.

A. N-(2,6-Dichlorophenyl)-11') -(l-methvl-2-pyrrolidinvlidene)-l-pyrrolidinecarboximidamidinium Methofluorosulfonate; To 6.83 g (0.02 mole) of N-(2,6-dichlorophenyl)-Ν'-(1-methyl2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide in dry CH2CI2 is added 2.70 g (0.023 mole) of methyl fluorosulfonate with stirring under N . The mixture is stirred overnight and then taken to dryness in vacuo leaving an oily residue which is triturated with ether to give crystals. Recrystallization from acetone and then from ethyl acetate gives the pure product, N-(2,6-dichlorophenyl)-Ν' -(l-methyl-2-pyrrolidinylidene)-1pyrrolidinecarboximidamidinium nethofluorosulfonate, m.p. 148-150°C. 3. N-(1-Msthyl -2-pyrrolidinylidene)-K1-phenyl-l-pyrrolidinecarboximidamidimium Methiodide: A solution of (0.05 mole) of N-(l-methyl-2-pyrrolidinylideneN'-pheny1-1-pyrrolidinecarboximidamide (Ex. ID) free base in 30 ml of acetone is treated with 0.05 mole of methyl iodide. After two days the crystals are collected and recrystallized from acetone affording pure N-(l-methyl-2-pyrrolidinylidene-N1phenyl-l-pyrrolidinecarboximidamidinium methiodide, m.p.(156) 162-164«C.

Anal. Calcd. for C17H25N4 I; c,49.52; H,6.11; N,13.59 Found : C,49.58; H,6.11; N,13.59 C. Similarly, treatment of, the product of example (ID) as the free base (0.05 mole) in ether (dry) with methyl fluorosulfonate (0.05 mole) rapidly gives an oily precipitate which crystallizes. Recrystallization from t-BuOH gives the product of Example (XVIIIB) as the corresponding methofluorosulfonate salt, m.p. 135.5-137°C. Λ A’SS®EXAMPLE XIX N-Phenyl-N1- (2-pyrrolidiftylidene)-l-pyrrolidine15 earboximidamide Hydroiodide: A solution of 0.07 mole of triethyloxonium fluoborate in dry CH2C12 is prepared in the usual way. To this solution is added 6.08 g (0.070 mole) of 2“pyrrolidinone. After stirring for 2 1/2 hrs., the mixture is basified with'NaOH (50%). with cooling (ice-water bath).

The organic layer-is separated and dried over K2CO3, thenfiltered and treated with 12.28 g (0.065 mole) of N-phenyl 1-pyrrolidinecarboximidamide. The CH2C12 solvent is evaporated while replacing .with tert-butanol and the resulting solution refluxed for 22 hrs. The reaction mixture is allowed to cool to room temperature and then neutralized with HI (47%), affording crystals of crude HI salt. Recrystallization from tert-butanol gives'pure salt, N-phenyl-N'-(2-pyrrolidinylidene)1-pyrrolidinecarboximidamide hydroiodide, m.p. 223-225°C dec. 52 EXAMPLE XX Ν-(l-Methyl-2-pyrrolidinylidene)-Ν1-phenyl-1-pyrrolidinecarboximidamide L-(+)-Tartrate; To 1.74 g (0.01 mole) Of phenyl isocyanide diohloride in dry st2o with cooling under N2 is added 0.71 g (0.01 mole) of pyrrolidine followed by 1.01 g (0.01 mole) of Et^N with stirring. The mixture is allowed to stir for 1 .1/2 hrs. and then filtered to remove precipitated EtgN’HCl. To the filtrate is added 1.96 g (0.02 mole) of l-methyl-2-iminopyrrolidine in an icewater bath. The resultant mixture is allowed to stir over10 night under N2 and then filtered to remove N-methyl-2-iminopyrrolidine hydrochloride, m.p. 182-188°C. The filtrate is evaporated to dryness in vacuo affording an oil which is-.dissolved in MeOH (10 ml) and treated with an equimolar amount of L(+)-tartaric acid. The resultant solution is concentrated while adding i-PrOH to give crystals. Recrystallization from isopropanol-acetonitrile gives the pure L-(+)tartrate salt, N-(l-methyl-2-pyrrolidinylidene)-N'-phenyl1-pyrrolidinecarboximidamide, m.p. 153-56°C.

EXAMPLE XXI Ν-(l-Methyl-2-pyrrolidinylidene)-Ν1-phenyl-1-pyrrolidinecarboximidamide L*(+)-Tartrate: To 0.99 g (0.01 mole) of l-methyl-2-pyrrolidone in dry benzene is added with, stirring at reflux temperature 1.26 g (0.01 mole) of dimethyl sulfate slowly. The reaction mixture is allowed to stir for 5 hrs. To the mixture is added.1.89 g (0.01 mole) of N-phenyl-l-pyrrolidinecarboximidamide slowly. The resulting mixture is allowed to stir overnight at room temperature. The mixture is taken to dryness in vacuo and then dis10 solved*in CH^C^ followed by conversion to the free base with NaOH (50%) in ice. The organic layer is dried (K2CO3), filtered and evaporated to dryness in vacuo, affording 2.7 g of an oil. The oil is dissolved in MeOH followed by addition of 1.5 g (0.01 mole) of L(+)-tartaric acid. Recrystallization from metnanol-isopropanol gives the product, N-(l-methyl-2pyrrolidinylid^ne)-N'-phenyl-l-pyrrolidinecarboximidamide L-(+j-tartrate, m.p. 153-156°C.

EXAMPLE XXII N-(l-Methyl-2-pvrrolidinvlidsne)-N1-phenvl-l-pvrrolidinecarboximidamide L-(+)-Tartrate: To a cooled solution of 1.98 g (0.02 mole) of l-methyl-2-pyrrolidone in dry toluene is added 3.95 g (0.04 mole) of phosgene. The resulting mixture is allowed to stir under N2 to room temperature over 45 minutes to give white crystals. The excess COC12 and solvent are removed with the aid of a filter stick (under N2). Fresh toluene is added, then removed under vacuum in order to remove residual phosgene. The crystals are washed in this way with fresh toluene two more times and then dissolved in dry CH2C12 followed by the addition of 1.89 g (0.01 mole) of N-phenyl-1-pyrrolidine earboximidamide and 1.01 g (0.01 mole) of triethylamine. The resulting mixture is stirred overnight under N,. The mixture . is taken to dryness in vacuo, the residue dissolved in CH2Cl2 and the latter solution treated with NaOH (50%) in ice. The organic layer, which,contains the free base form of the product is separated, dried over anhydrous K2CO3, filtered and taken to dryness in vacuo affording an oily residue. The oil is dissolved in isopropanol followed by addition of L-(+)-tartaric acid to about pH 6-7. The resulting crystals are recrystallized from' isopropanol to give pure product, N-(l-methyl-2pyrrolidinylidene)-Ν'-phenyl-l-pyrrolidinecarboximidamide L(+)-tartrate, m.p. 155-156°C.

Bit.

EXAMPLE XXIII N-(l-Methyl-Z-pyrrolidinylidene)-N'-phenyl-l-pyrrolidinecarboximidamide Hydro iodide; To 2.57 g (0.01 mole) of 1methyl-2-methylthio-l-pyrrolinium iodide in t-BuOH is added 1.89 g (0.01 mole) of N-phenylrl-pyrrolidinecarboximidamide.

The resulting mixture is allowed to heat under reflux overnight.Evolving MeSH is trapped in concentrated NaOH .solution. Cooling and scratching gives 3.65 g (92%) of crude product which upon recrystallization from t-BuOH gives pure N-(l-methyl-2-pyrrolidineylidene-N'-pheny1-1-pyrrolidinecarboximidamide hydro10 iodide, m.p.206-207°C, identical in all respects with the product of Example (ID) EXAMPLE XXIV N-(l-Methyl-2-pyrrolidinylidene-N1-phenyl-l-pyrrolidinecarboximidamide L (+)-Tartrate; To 1.29g (0.0075 mole) of 2,2-diethoxy-l-methylpyrrolidine in dry benzene is added 1.42g (0.0075 mole) of N-pheny1-1-pyrrolidinecarboximidamide. The mixture, after refluxing overnight, is taken to dryness in .vacuo. The residue ip treated with dilute hydrochloric acid (10%) then basified with cold NaOH (20%) and ,the free product is extracted with ether. The dried (K^CO^) extracts are taken to dryness in vacuo and the residual oil is taken up ini-PrOH and treated IQ with one mole equivalent of L-(+)-tartaric acid. After recrystallization from MeOH-i-PrOH, pure N-l-methyl-2-pyrrolidinylideneN'-phenyl-l-pyrrolidinecarboximidamide L(+)tartrate is obtained; m.p. 153-156°C. *4702 Γ ΛΛΜι'ι.Ι \W -i \ X 'i’i'w ulijf i, £ fc*y ί Λ’-ί »ii% ) *' .carboximiaamide.is converted to the following organic and inorganic pharmaceutically acceptable acid addition salts by conventional treatment with each of the respective indicated . acids: fumarate, m.p. 156-57°C; phosphate, m.p. 200-01°C (dec.); hydrobromide, m.p. (206) 207-09°C; oxalate, m.p. 129-3l°C; pamoate, m.p. 253-56°C (dec.); nitrate, m.p. 17O-71°C (slight dec.); maleate, m.p. 115-17°C; and n-hydroxybenzoate, m.p. 179-80°C. 441?®3 • 1 EXAMPLE XXVI ' ' A. N-Phenyl-l-pyrrolidinecarboximidamide Hydrochloride; and B. 1-(l-Methyl-2-pyrrolidinylidene)pyrrolidinium Iodide l ..-- -.Hydrate. ' A. -. The mother liquor -set aside in Example I-D is taken to 5 dryness in vacuo and the residue is taken up in methylene chloride and basified with cold’dilute NaOH. Extraction with CH2C12 (200 ml)' is repeated three times. The combined organic extracts are dried over anhydrous KgCOg, filtered, and taken to dryness in vacuo, leaving a brown heavy sirup.

Extraction of the sirup by. trituration with hexane (2x200 ml) and with ether (3x200 ml) leaves a dark residue (set aside).

The organics layers are combined and treated with charcoal, filtered, and taken to dryness in vacuo giving a brown sirup - which is converted, to the HCl salt and recrystallized from . isopropanol-ether to give N-phenyl-l-pyrrolidinecarboximidamide hydrochloride,, ,m.pi 181-84°C.

Anal. Calc'd. for C1£H15N3*HC1: C, .58.53; H, 7.15% ' Found: C, 58.59; H 7.08% B. The dark residue set aside'above is taken up in isopropanol and treated with a large amount of charcoal. Filtration followed by solvent removal in vacuo gives a dark brown glassy material which, upon trituration with acetone with concommitant charcoaling,, affords white crystals of l-(l-methyl-2-pyrrolidinylidene)pyrrolidinium iodide, which forms a hydrate with about 1/4 mole HgO; m.p. (98) 108-110°C. On a humid day. the crystals will take up excess water and melt but will, solidify again when the'humidity drops.

Anal. Calc'd. for C19H17N2+-I~-l/4 H20 : C, 37.98, H, 6.02; I; 44.58 H20, 1.58% Found: C, 38.15; H, 6.11; I, 45.25,. H20, 1.13% - . ' '.58 EXAMPLE XXVII 44783 N-(4-Aminophenvl)-N'-(l-methyl-2-pvrrolidinvlidene)-lpyrrolidinecarboximidamide Hydrobromide: N-(1-methyl-2pyrrolidinylidene)-Ν'-(4-nitrophenyl)-l-pyrrolidinecarboximidamide(product 4 of Example XVII), 2.46g (0.0078 mole) in 50 ml of absolute ethanol in hydrogenated (ca. 3 atmospheres) on a Parr shaker over Raney nickel catalyst, uptake of hydrogen is complete after ca. 0.5 hr. The catalyst is separated by filtration and washed with ethanol. The combined filtrates are evaporated in vacuo. The residue is dissolved in ethanol and neutralized with one equivalent of agueous HBr solution (48%). The resulting solid is recrystallized from ethanolether to give pure N-(4-aminophenyl)-Ν'-(l-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide hydrobromide, m.p. 241-241.5’C.

Anal. Calcd Pound for C, Η, B. HBr: C,52.46; H,6.60; N,19.12. lo 23 7 : C,52.44? H,6.60; N,19.09.

EXAMPLE XXVIII N-(4-Acetylaminophenvl)-Ν’-(l-methyl-2-pvrrolidinylidene1-pyrrolidinecarboximidamide Hydrobromide: N-(4-aminophenylN'-(l-methyl-2-pyrrolidinylidene-l-pyrrolidinecarboximidamide (The product of Example XXVII) as its free base, 3.4g (0.0119 mole) is heated on a steam bath with 25 ml of acetic anhydride for ca. 1 hr. After this time the reaction mixture is diluted with ethanol and heated for another hour. The volatile components are removed in vacuo and the residue is treated with dilute agueous NaOH and extracted into methylene chloride. ν ·. ? 'ζ • 44*?β0 After drying the extracts over I^CO^, filtration and solvent removal affords a residual oil which is converted to its corresponding HBr acid addition salt in ether-ethanol. Re' crystallization from ethanol-ether gives the pure product N(4-Ac.etylaminophenyl)-N'-(l-methyl-2-pyrrolidinylidene-l15 , pyrrolidinecarboximidamide, m, p. 246-247°C. • >. ' EXAMPLE XXIX • N-(l-Methyl-2-pyrrolidinylidene)-N1-(4-methylsulfonylphenyl) ^-morpholinecarbOximidamlde: To 1.98g (0.0006 mole) of N-(4methylthiophenyD-N1 (l-methyl*2-pyrrolidinylidene)-4-morpholinecarboximidamide (compound 31 of Example XV) as the free base S is dry methylene-chloride, cooled to 0°, is added with.stirring 3.6g (0.018 mole) of m-chloroperoxybenzoic acid such that the temperature does not rise above 5°C. - The mixture Is allowed to stir at these· temperatures for 0.5 hr. then is washed respectively with saturated solutions of NaHCO^ (3 x 40 ml) and NaCl (3 x 35 ml). The organic layer is dried (K2CO3) then filtered (filter aid) followed by evaporation to near dryness in vacuo. Dilution With MeOH affords some insoluble material which is filtered off and discarded. The filtrate is. evaporated to near dryness on the steam bath. Dilution with ether affords crystals, m.p. 160-166eC, Recrystallization from ether gives pure N-(l-methyl-2-pyrrolidinylidene)-Ν'-(4-methylsulfonylphenyl) •-4-morpholinecarboximidamide, m.p.(165) 167-170°C.

-- Anal. Calcd. for- C^H^O^S: C,56.03; H,6.64 Found ; C,56.05; H,6.69 447qz EXAMPLE XXX N-(l-Methyl-2-pyrrolidinylidene)-Ν’-(4-methylsulfinylphenyl) 4-morpholinecarboximidamide: To a stirring solution of 1.98g (0.006 mole) of N-(4-methylthiophenyl)-N'-(l-methyl-2-pyrrolidinylidene)-4-morpholinecarboximidamide(compound 31 of Example XV) as the free base in CH2C12 at 5° is added 1.22 g (0.006 mole) of m-chloroperoxybenzoic acid such that the temperature is maintained, at 5°. The reaction mixture is then allowed to warm to room temperature and stirred for two more hours. The organic layer is washed respectively with saturated NaHCO-j solution(3x30 ml) and saturated NaCl solution (2x30 ml) then dried over K2CO3(anhyd). Filtration, solvent removal in vacuo, and treatment of the residue with ether-hexane gives the crude product which is recrystallized from ether-hexane to give pure N-(1-methyl-2-pyrrolidinylidene)-Ν'-(4-methylsulfinylphenyl)15 4-morpholinecarboximidamide, m.p. (115)117-120eC.

Anal. Calcd. for C^H^NjO S: C,58.60} H,6.94 Found ·. C,58.58, H,6.91 EXAMPLE XXXI N-(4-Hydroxyphenyl)-N1-(l-methyl-2-pyrrolidinylidetie)1-pyrrolidinecarboximidamide Hydroiodide: A solution of 26?6g (0.Q71 mole) of N-(l-methyl-2-pyrrolidinylidene)-N'-(4-benzyloxyphenyl)-l-pyrrplidinecarboximidamide (product 27 of Example XV) as its corresponding free base in 50 ml of acetic acid is placed in a Parr shaker and hydrogenated at ca. 3 atmospheres over 10¾ Pd/C for ca. 2 hrs., or until K2 uptake is complete, at room temperature. The reaction mixture is filtered and the solvent ’ . 44^* is removed- in vacuo affording, a viscous oil which is taken up 10 in acetone and treated with one equivalent of HI(concentrated aqueous). The crude crystals are recrystallized from, methanolacetone-ether to give pure N-(4-hydroxyphenyl)-Ν'-(l-methyl-2pyrrolidlnylidene)-l-pyrrolidinecarboximidamide hydroiodide, m.p·. 174-178°C.

Anal. Calcd. for C^^^O-HI: C,46.39.,- H,5.60; N,13.52 Pound : C,46.62; H,5.59,- N,13.63 . . ..EXAMPLE XXXII · H-(4-Acetoxyphenyl)-Ν'-(l-methyl-2-pyrrolidinylidene)-1pyrrolidinecarboximidamide Hydriodide: Twelve grams (0.20 mole) of glacial acetic acid is added slowly to a solution of 5.15g (0.0124 mole) of N-(4-hydroxyphenyl)-Ν'-l-methyl-25 pyrrolidinyiidene)-l-pyrrolidinecarbcximidamide hydriodide(the compound of Example XXXI) and 41.2g (0.20 mole of Ν,Ν*-dicyclohexylcarbodiimide in 400 ml of acetone. The reaction mixture is stirred at room temperature under nitrogen for 3 days. . Ν,Ν'-Dicyclohexylures is removed by filtration and the filtrate 10 concentrated to dryness in vacuo to give an amber oil. The several triturations with ether a yellow solid is obtained. Recrystallization from acetone-ether gives a white solid, m.p. (188)195-197°C. Further recrystallization. from methanol-acetone ether affords pure N-(4-acetoxyphenyl)-Ν'-(l-methyl-2-pyrroli15 dinylidene)-1-pyrrolidinecarboximidamide Hydriodide as a white solid, m.p. 196-199°C. . . ' Anal. Calcd. for ’ HI: C,47.38; H,5,52; N,12.28 Found ; C,47.31; H,5.57; N,12.26

Claims (65)

1. CLAIMS:1. A heterocyclic derivative of guanidine having the general formula: (CH 2 ) n NR (I) 5 wherein: n is the integer 1, 2 or 3; R^ is a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, an alken-2-yl group having from 3 to 5 10 carbon atoms, a hydroxyloweralkyl, aralkyl or an aryl group; Rg is a hydrogen atom, an alkyl group having from 1 to 6 carbon atoms or an aryl group; Rg is a hydrogen atom, an alkyl group having from 1 tc? 8 15 carbon atoms or an aryl group; R^ is a hydrogen atom, a methyl or an ethyl group; Rg is an alkyl group having from 1 to 4 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, an *' aralkyl or an aryl group; or R. 20 -Nr taken together represents a 3- to 7-membered saturated R 5 heterocycl'fc ring; provided that when -NR^Rg represents a six-membered ring, (i) the ring may, if desired, be interrupted by an oxygen or sulfur atom or by an additional nitrogen atom, which additional nitrogen 44793 atom may be substituted with a loweralkyl, phenyl or benzyl group, or (ii) the ring may be substituted with a loweralkyl group, at a carbon atom other than one immediately adjacent the nitrogen atom which is bonded to the carboximidamide function; and : R is an alkyl group having from 4 to 10 carbon atoms; a cycloalkyl group having from 5 to 8 carbon atoms; a bicyeloalkyl group having from 7 to 10 carbon atoms; a bicycloalkenyl group having from 7 to 10 carbon atoms; a tricycloalkyl group having 9 or 10 carbon atoms; I- 1 adamantylmethyl;a tricycloalkenyl group having 9 or 10 carbon atoms; an arylalkyl group in which the aryl group is a phenyl or naphthyl group and the alkyl group has from 1 to 4 carbon atoms; α,a-tetramethylenephenethyl; a diphenylalkyl group in which the alkyl group has 1 or 2 carbon atoms; naphthyl; fused diaryIcycloalkenyl; fused arylcycloalkyl; a phenylcycloalkyl group in which the cycloalkyl group has from 5 to 7 carbon atoms; a cycloalkylcycloalkyl group in which each cycloalkyl group has from 5 to 7 carbon atoms: phenyl; methylenedioxyphenyl; a phenyl group substituted l with'from 1 to 3 substituents each selected from a halogen atom, a loweralkyl or loweralkoxy group; a phenyl group substituted with an amino, dimethylamino, methylethylamino, diethylamino, loweralkanoylamino, thioloweralkyl, sulfinylloweralkyl, sulfonylloweralkyl, trifluoro11 . methyl, hydroxy, benzyloxy, loweralkanoyloxy, loweralkanoyl I . or nitro group; 3-pyridyl; or a 3-pyridyl group substituted at the ring carbon atoms with 1 or 2 halogen atoms; 64. loweralkyl or loweralkoxy groups.

2. A heterocyclic derivative o£ guanidine having the general formula: R 6 5 wherein: n is the integer 1 or 2; Rg is a loweralkyl, allyl, hydroxyloweralkyl or benzyl group; ' R ? is a methyl or ethyl group; ° Rg is a loweralkyl, cyclopentyl or cyclohexyl group; -NR^Rg taken,together is a pyrrolidino, piperidino, morpholino or thiomorpholino group; Rg is a 1-adamantyl, 1,1,3,3-tetramethyl-butyIphenyl; methylenedioxyphenyl, phenyl substituted with from 5 1 to 3 substituents each selected from a halogen atom, a loweralkyl or loweralkoxy group; or a phenyl group substituted with an amino, dimethylamino, methylethylamino, diethylamino, loweralkanoylamino, thioloweralkyl, sulfinylloweralkyl, trifluoromethyl, hydroxy, benzyloxy, 0 loweralkanoyloxy, loweralkanoyl or nitro group; R^ o is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms; and R^j_ is a hydrogen atom or an alkyl group of 1 to 3 carbon atoms; provided that at least one of R^ and is a tr-.-Γ 'Λ 44792 ί. hydrogen atom.

3. N-(I-Methyl-2-pyrrolidinylidene)-N 1 -phenyl-1pyrrolldihecarboximidamide.

4. · N-(l-Methyl-2-pyrrolidinylidene)-Ν'-pheny1-45 morpholinecarboximidamide. t 1 .

5. N-(l-Methyl-2-pyrrolidinylidene)-N'-p-methoxyphenyl-l-pyrrolidinecarboximidamide.

6. N-(l-Methyl-2-piperidinylidene-N'-pheny1-1pyrrolidinecarboximidamide. 1-°

7. N-(l-Methyl-2-pyrrolidinylidene)-N'-(l,1,3,3tetramethylbutyl)-l-pyrrolidinecarboximidamide.

8. N-(l-Allyl-2-pyrroIidinylidene)-N , -phenyl-lpiperldinecarboximidamide. --:.

9. N-(l-Methyl-2-pyrrolidinylidene)-Ν'-cyclopentyl15 Ν'-methyl-N-phenylguanidine.

10. N-(l-Methyl-2-pyrrolldinylidene)-N'-phenyl-4thiamorpholinecarboxirnidamide.

11. N-(l-Methyl-2-pyrrolidinylidene)-N , -phenyl-lpiperidinecarboximidamide.

12. N-(4-Fluorophenyl)-N'- (l-methyl-2-pyrrolidinylidene) l-pyrrolidinecarboximidamide.

13. N-(4-MethyIphenyl)-N'- (1-methy1-2-pyrrolidinylidene) l-pyrrolidinecarboximidamide.

5. 14. N-(l-Methyl-2-pyrrplidinylidene)-Ν'-(3,4-methylenedioxyphenyl)-1-piperidinecarboximidamide.

15. N-(3-Chlorophenyl)-N'-(l-methyl-2-pyrrolidinylidene) 4-morpholinecarboximidamide.

16. N-Cyclopentyl-N-methyl-N'- (3-methyIphenyl)-N1° (l-methyl-2-pyrrolidinylidene)guanidine.

17. N-Cyclohexyl-N'-(4-methoxyphenyl)-N-methyl-N(l-methyl-2-pyrrolidinylidene)guanidine.

18. N-(4-Acetyloxyphenyl)-N 1 -(l-methyl-2pyrrolidinylidene)-l-pyrrolidinecarboximidamide. 15

19. N-(4-Methylphenyl)-N'-(l-methyl-2-pyrrolidinylidene) 4-morpholiriecarboximidamide.

20. N-(4-Methylphenyl)-Ν'-(l-methyl-2-pyrrolidinylidene) 4-thibmorpholinecarboximidamide.

21. N-(3-Methylphenyl)-Ν'-(l-methyl-2-piperidinylidene)20 4-morpholinecarboximidamide. ¢47 88

22. N-(3-Methylphenyl)-Ν'-(l-methyl-2-pyrrolidinylidene) 4-morpholinecarboximidamide.

23. N-(4-Chlorophenyl)-N r -(1-methyl-2-pyrrolidinylidene) 1-pyrrolidinecarboximidamide. 5

24. 4-Methyl-N-(l-methyl-2-pyrrolidinylidene)-Ν'pheny1-1-piperazinecarboximidamide.

25. N-(1-Adamantyl)-Ν' -(l-methyl-2-pyrrolidinylidene)1-pyrrolidinecarboximidamide.

26. N-(l-Methyl-2-pyrrolidinylidene)-N'-(2-naphthyl)10 1-pyrrolidinecarboximidamide.

27. 4-3?henyl-N-(l-methyl-2-pyrrolidinylidene)-N'pheny1-1-piperazinecarboximidamide.

28. N-Cyclohexyl-N'-(l-methyl-2-pyrrolidinylidene)1-pyrrolidinecarboximidamide. b 15 -

29. N-(l-Methyl-2,3,4,5,6,7-hexahydroazepinylidene)N'-phenyi-l-pyrrolidinecarboximidamide.

30. N-(l-Ethyl-2-pyrrolidinylidene)-N'-phenyl-lpyrrdlidinecarboximidamide.

31. N-(Diphenylmethyl)-N'- (l-methyl-2-pyrrolidinylidene) 20 1-pyrrolidinecarboximidamide. 4 4 783

32. N-Cyclohexyl-N-methyl-N'- (l-methyl-2pyrrolidinylidene)-N-(l-naphthyl)guanidine.

33. N-(l,5-Dimethyl-2-pyrrolidinylidene)-N'-phenyl1-pyrrolidinecarboximidamide. 5

34. N,N-“Diethyl-N*~{l»iiaethyI-2“pyrrolidinylidene)NP'-phenylguanldlne.

35. N-(l-Ethyl-2-pyrrolidinylidene)-N'- (4-methoxyphenyl)-1-pyrrolidinecarboximidamide.

36. N-(l-Benzyl-2-pyrrolidinylidene)-N'-phenyl-4 1° morpholinacarboximidamide.

37. Ν-Γ1-(2-Hydroxyethyl)-2-pyrrolldinyIidene7-N phenyl-4-morpholinecarboximidamide.

38. N-(SH-Fluoren-9-yl)-Ν’-(l-methyl-2pyrrolidinylidene)-1-pyrrolidinecarboximidamide. 15

39. N-Diphenylmethyl-N’-(l-methyl“2-piperidinylidene)4-morpholtnecarboximidamide.

40. N- (3-MethoxyphenyD-N* - (l-raethyl-2-pyrrolidinylidene) l-piperidinecarboxiimidamide.

41. N-(3,4-Dimethoxyphenyl)“N'~(l-methyl-220 pyrrolidinylidene)-1-pyrrolidinecarboximidamide. ¢69.83

42. N-(l-Methyl-2-pyrrolidinylidene)-Ν'-(4methylthiophenyl)-4-morpholinecarboximidamide.

43. Ν-(l-Methyl-2-pyrrolldinylidene)-N'-phenyl-4(2,6-dimethyl)morpholinecarboximidamide. 5

44. N-(4-Benzyloxypheayl)-N*-(l-methyl-2pyrrolidinylidene) ’l-pyrrolidinecarboximidamide.

45. N-(1-Allyl-2-pyrrolidinylidene)-N'- (3mathylphenyl)-4-thiomorpholinecarboximidamidG.

46. N-(3-Methoxyphenyl)-N* -(l-methyl-210 pyrrolidinylidanej-i-thiomorgholinecarbosiraidamids.

47. A pharmaceutically acceptable acid addition salt of a compound as claimed in any one of claims 1 to 46.

48. N-(2,6-Dichlorophenyl)-N 1 - (l-methyl-2pyrrolidinylidene)-1-pyrrolidinecarboximidamidinuim 15 Methofluorosulfonate.

49. · A quaternary salt of a compound as claimed in any One of claims 1 to 45.

50. A pfocosQ for preparing a heterocyclic derivative of guanidine-having the general formulas 7 CL 44702 (CH_) NR 2. η «ί Ν— C— Ν ' (I) or a pharmaceutically acceptable acid addition or quaternary salt thereof, wherein n, R. , R., R,, R., R_, — 1 Z J 4 3 / R -N and R are as defined in claim 1 which process comprises (a) reacting a compound of the formula: (III) wherein R^, R 2 , R 3 and n are as defined in claim 1, X is a θ θ methoxy or ethoxy group and Y is either BF^ or OSO 2 F with a compound of the formula: NR II H 2 N-C-NR 4 R 5 (IV) in an anhydrous organic solvent, in order to prepare a compound of the formula: (V) and thereafter converting the compound -(V) to the corresponding base form (I) by conventional means; or (b) reacting a compound of the formula; 5 wherein R^, Rj, R 3 and — are as defined in claim 1, and Θ is an anion witha compound of the formula (IV) as defined above, in an anhydrous organic solvent in order to prepare the corresponding salt of compound (I) and thereafter converting the latter compound to the .0 corresponding base form (I) by conventional means; or (c) reacting the free base form of compound (III) (wherein is hydrogen), the base having the formula: -Wn (IX) -&· with compound (IV), in an anhydrous organic solvent, in order to prepare a compound of the formula; tautomers ^N H n-c-nr 4 r 5 , (CH„) NR. 2 η ii -n-c-nr.r, H ' (X) or (d) reacting a compound of the formula: (CH,) 2 n (XII) -OMe OSOgMe wherein n, R^, Rg and Rg are as defined in claim 1 with a compound of the formula (IV) in an anhydrous organic solvent, in order to prepare the corresponding methylsulfate salt of formula (I), which may be transformed into the corresponding free base of formula (I); or (e) reacting a compound of the formula: .(CHg) n loweralkyl loweralkyl (Xlla) wherein n, R^, Rg and Rg are as defined in claim 1 with a compound of the formula (IV) in a suitable anhydrous organic solvent in order to prepare the free base of formula (I); or (f) reacting a compound of the formula: wherein n, R^, Cl (XIII) Rg and Rg are as defined in claim 1, with a -V 1compound Of the formula (IV) in an anhydrous aprotic solvent in order to prepare said compound (I); or (g) reacting a compound of the formula: n SR’ N—C=NR · HZ (XVII) wherein R' is an ethyl or methyl group, and HZ is an acid with a compound of the formula HNR^R^' wherein R^ is as defined in claim 1 and R ' is as the definition of R, 5 5 given in claim 1 but other than phenyl or substituted phenyl, in order to prepare compound (I) in acid addition form and converting this compound to the base form; or (h) reacting two molar equivalents of a compound of the formula: (XIV) wherein ii, R^, R^ a ud R 3 are as defined in claim 1 with a 15 compound of the formula: NR ; . , ll C1-C-NR 4 R 5 (XVIII) wherein R 4 and R^ are as defined in claim 1 in order to prepare a compound of the formula (I) in base form; and, if desired, preparing pharmaceutically acceptable acid addition and quaternary salts of the products of steps (a) to (h).

51. A process as claimed in claim 50 wherein the 5 salt form of compound (I) produced is converted to the I base form by treatment with alkali.

52. A process as claimed in claim 50 wherein in

Q Aft process (b) Y is an 1 , 0S0 2 F , methylsulfate, tosylate or mesylate anion. 6. 10 53. A process as claimed in claim 50 wherein in process (c) the reaction between the compounds of formula (IX) and formula (IV) is carried out at an elevated temperature.

54. A process as claimed in claim 50 wherein in 7. 15 process (d) the reaction between the compounds of formula (XII) and the compound of formula (IV) is carried out at a temperature in the range of from 25° to 1OO°C.

55. A process as claimed in claim 50 wherein in process (f) the anhydrous aprotic solvent is an aromatic 2° hydrocarbon.

56. A process as claimed in claim 50 wherein in process (g) the reaction is carried out in a lower alkanol solvent at reflux temperature.

57. A process for preparing N-(l-methyl-2t _ ’ - pyrrolidinylidene)-N’-phenyl-l-pyrrolidinecarboximidamide which comprises reacting methyl N-(l-methyl-25 pyrrolidinylidene)-Ν'-phenylcarbamimidothioate hydroiodide with pyrrolidine and converting the product to the free base. - - .-r .

58. A process for preparing N-(l-methyl-2pyrrolidinylidene)-N'-phenyl-4-morpholinecarboximidarnide •® which comprises reacting methyl N-(l-methyl-2pyrrolidinylidene)-N 1 -phenylcarbamimidothioate hydroiodide With morpholine and converting the product to the free base.

59. A process for preparing N-(l-methyl-2 5 pyrrolidinylidene)-N’-phenyl-4-thiamorpholinecarboximidamide which comprises reacting l-methyl-2-pyrrolidinone with methyl fluorosulfonate, then reacting the product Λ with N-phenyl-4-thiamorpholinecgrboximidamide and converting the product to the free base. 10

60. A process for preparing. N-(4-fluorophenyl)N'-(l-methyl-2-pyrrolidinylidene)-1-pyrrolidinecarboximidamide which comprises reacting N-l-methyl-.2pyrrolidinylidene-Ν'-£-fluorophenylthiourea with pyrrolidine and converting the product to the free base.

61. A process for preparing N-(4-methylphenyl)-Ν’(1-methy1-2-pyrrolidinylidene)-1-pyrrolidineoarboximidamide which comprises reacting triethyl oxonium fluoborate with l-methyl-2-pyrrolldinone, reacting the product with N-(45 methylphenyl)-1-pyrrolidinecarboximidamide and converting the product to the free base.

62. A process for preparing N-(3-chlorophehyl)-N'(l-methyl-2-pyrrolidinylidene)-4-morpholinecarboximidamide which comprises reacting triethyl oxonium fluoborate with 10 1-methy1-2-pyrrolidinone, reacting the product with N-(3chlorophenyl)-4-morpholinecarboximidamide and converting the product to the free base.

63. A'process as claimed in claim 50 substantially as hereinbefore described with reference to any one of 15 Examples xiv to xxv, or xxvn to xxxn.

64. A compound of formula (I) as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 50 to 63.

65. ‘ A pharmaceutical composition which comprises at 20' least one compound of formula(I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or · carrier.